B01: Antithrombotic agents
Antithrombotic agents either stop blood clots from forming, or dissolve clots that have already formed.
How do antithrombotics work?
The group splits into three kinds of drug, each acting on a different part of clotting.
Anticoagulants slow down the chain of enzyme reactions that forms a clot (coagulation cascade).
- Warfarin (B01AA03), a vitamin K antagonist, suppresses the synthesis of clotting factors [1].
- Heparins, such as heparin (B01AB01) and enoxaparin (B01AB05), act as cofactors for the body’s own inhibitors of coagulation, antithrombin and heparin cofactor II [2].
- The direct oral anticoagulants inhibit a single clotting enzyme directly. Dabigatran etexilate (B01AE07) inhibits thrombin [3], and apixaban (B01AF02) inhibits factor Xa [4].
Platelet aggregation inhibitors stop platelets from clumping together. Acetylsalicylic acid (aspirin, B01AC06) works by inhibiting the production of thromboxane A2 in platelets, while the P2Y12 antagonists, such as clopidogrel (B01AC04) and ticagrelor (B01AC24), dampen the platelets’ response to adenosine diphosphate (ADP) [5].
Enzymes dissolve clots that have already formed. Alteplase (B01AD02) is tissue plasminogen activator, and tenecteplase (B01AD11) is a variant engineered from it [6].
Efficacy
For warfarin, the effect is measured with a coagulation test that gives continuous values, the prothrombin time [1]. For apixaban, anti-factor Xa activity rises linearly with plasma concentration, and it changes more, and varies less, than traditional clotting tests such as the international normalized ratio (INR) [4]. In an exposure-response analysis of ticagrelor in 20,942 patients with a prior heart attack (myocardial infarction), the hazard of cardiovascular death, myocardial infarction or stroke was related to individual ticagrelor exposure rather than dose [7].
For warfarin, the effect follows the turnover of the clotting factors rather than the plasma concentration. The existing factors have to be cleared first, so at a constant warfarin concentration the effect takes about 3 days to stabilize. Models of warfarin therefore combine a pharmacodynamic model for the inhibition of clotting factor synthesis with a model for the synthesis and degradation of the clotting factors. An Emax model is preferred on theoretical grounds, but it has not clearly performed better than linear, log-linear or power models [1]. A joint model of the vitamin K-dependent clotting factors and anticoagulation proteins linked an inhibitory Emax model to a turnover model for these proteins [8]. Clopidogrel binds the P2Y12 receptor irreversibly, so platelet reactivity recovers slowly and the effect outlasts the drug [9]. Indirect response models, in which the drug acts on the production or the loss of the response, describe effects that lag concentration in this way [10].
Dabigatran and apixaban behave differently. They inhibit their target enzyme directly, and their effect on clotting tests follows plasma concentration with little delay [3,4].
Safety
For edoxaban in blood clots in the veins (venous thromboembolism), recurrence fell as concentration rose, but no significant exposure-response relationship was found for clinically relevant bleeding [11].
Higher plasma concentrations of the direct oral anticoagulants have been associated with more bleeding. In a systematic review of their population PK models, renal function was the main covariate on clearance for all four, while age and inhibitors of P-glycoprotein or CYP3A4/5 were found in fewer models, and body weight rarely [12]. For ticagrelor after myocardial infarction, predicted efficacy was similar at 60 and 90 mg, while predicted major bleeding rose slightly [7].
Heparins are associated with a low platelet count (thrombocytopenia) and with raised liver enzymes (transaminases). In a small subset of patients the thrombocytopenia is severe, and it generally resolves when the drug is withdrawn [2].